Specific knockout of Sox2 in astrocytes reduces reactive astrocyte formation and promotes recovery after early postnatal traumatic brain injury in mouse cortex.

In response to central nervous system (CNS) injury, astrocytes go through a series of alterations, referred to as reactive astrogliosis, ranging from changes in gene expression and cell hypertrophy to permanent astrocyte borders around stromal cell scars in CNS lesions. The mechanisms underlying injury-induced reactive astrocytes in the adult CNS have been extensively studied. However, little is known about injury-induced reactive astrocytes during early postnatal development. Astrocytes in the mouse cortex are mainly produced through local proliferation during the first 2 weeks after birth. Here we show that Sox2, a transcription factor critical for stem cells and brain development, is expressed in the early postnatal astrocytes and its expression level was increased in reactive astrocytes after traumatic brain injury (TBI) at postnatal day (P) 7 in the cortex. Using a tamoxifen-induced hGFAP-CreERT2; Sox2flox/flox ; Rosa-tdT mouse model, we found that specific knockout of Sox2 in astrocytes greatly inhibited the proliferation of reactive astrocytes, the formation of glia limitans borders and subsequently promoted the tissue recovery after postnatal TBI at P7 in the cortex. In addition, we found that injury-induced glia limitans borders were still formed at P2 in the wild-type mouse cortex, and knockout of Sox2 in astrocytes inhibited the reactivity of both astrocytes and microglia. Together, these findings provide evidence that Sox2 is essential for the reactivity of astrocytes in response to the cortical TBI during the early postnatal period and suggest that Sox2-dependent astrocyte reactivity is a potential target for therapeutic treatment after TBI.

Dynamic Changes in Neuroglial Reaction and Tissue Repair after Photothrombotic Stroke in Neonatal Mouse.

Perinatal and neonatal ischemic stroke is a significant cause of cognitive and behavioral impairments. Further research is needed to support models of neonatal ischemic stroke and advance our understanding of the mechanisms of infarction formation following such strokes. We used two different levels of photothrombotic stroke (PTS) models to assess stroke outcomes in neonatal mice. We measured brain damage, dynamic changes in glial cells, and neuronal expression at various time points within two weeks following ischemic injury. Our results from 2,3,5-Triphenyltetrazolium chloride (TTC) staining and immunofluorescence staining showed that in the severe group, a dense border of astrocytes and microglia was observed within 3 days post infarct. This ultimately resulted in the formation of a permanent cortical cavity, accompanied by neuronal loss in the surrounding tissues. In the mild group, a relatively sparse arrangement of glial borders was observed 7 days post infarct. This was accompanied by intact cortical tissue and the restoration of viability in the brain tissue beyond the glial boundary. Additionally, neonatal ischemic injury leads to the altered expression of key molecules such as Aldh1L1 and Olig2 in immature astrocytes. In conclusion, we demonstrated the dynamic changes in glial cells and neuronal expression following different degrees of ischemic injury in a mouse model of PTS. These findings provide new insights for studying the cellular and molecular mechanisms underlying neuroprotection and neural regeneration after neonatal ischemic injury.

Sex-specific hypothalamic neuropathology and glucose metabolism in an amyloidosis transgenic mouse model of Alzheimer's disease.

BACKGROUND: Amyloid toxicity and glucose metabolic disorders are key pathological features during the progression of Alzheimer's disease (AD). While the hypothalamus plays a crucial role in regulating systemic energy balance, the distribution of amyloid plaques in the preoptic, anterior, tuberal, and mammillary regions of the hypothalamus in AD mice, particularly across both sexes, remains largely unclear. Our ongoing research aims to explore hypothalamic neuropathology and glucose metabolic disturbances in a well-described APP/PS1 mouse model of AD. RESULTS: Immunocytochemical staining revealed that Old-AD-Female mice exhibited a greater hypothalamic Amyloid ß (Aß) burden than their Old-AD-Male counterparts, with the mammillary bodies showing the most severe accumulation. Analysis of ionized calcium binding adaptor molecule 1 (IBA1) immunoreactivity and Iba1 mRNA indicated differential microgliosis based on sex, while tanycytic territory and ZO-1 tight junction protein expression remained stable in AD mice. Moreover, sex-specific peripheral glucose metabolic parameters (random and fasting blood glucose) seemed to be exacerbated by age. Old AD mice of both sexes exhibited limited hypothalamic activation (c-Fos + cells) in response to blood glucose fluctuations. Hypothalamic Glut 1 expression decreased in young but increased in old female AD mice compared with age-matched male AD mice. Pearson correlation analysis further supported a negative correlation between hypothalamic Aß load and random blood glucose in old AD groups of both genders, shedding light on the mechanisms underlying this amyloidosis mouse model. CONCLUSION: Aged APP/PS1 mice exhibit sex-specific hypothalamic neuropathology and differential glucose metabolism, highlighting distinct pathological mechanisms within each gender.

Temporal-spatial Generation of Astrocytes in the Developing Diencephalon.

Astrocytes are the largest glial population in the mammalian brain. However, we have a minimal understanding of astrocyte development, especially fate specification in different regions of the brain. Through lineage tracing of the progenitors of the third ventricle (3V) wall via in-utero electroporation in the embryonic mouse brain, we show the fate specification and migration pattern of astrocytes derived from radial glia along the 3V wall. Unexpectedly, radial glia located in different regions along the 3V wall of the diencephalon produce distinct cell types: radial glia in the upper region produce astrocytes and those in the lower region produce neurons in the diencephalon. With genetic fate mapping analysis, we reveal that the first population of astrocytes appears along the zona incerta in the diencephalon. Astrogenesis occurs at an early time point in the dorsal region relative to that in the ventral region of the developing diencephalon. With transcriptomic analysis of the region-specific 3V wall and lateral ventricle (LV) wall, we identified cohorts of differentially-expressed genes in the dorsal 3V wall compared to the ventral 3V wall and LV wall that may regulate astrogenesis in the dorsal diencephalon. Together, these results demonstrate that the generation of astrocytes shows a spatiotemporal pattern in the developing mouse diencephalon.

Krüppel-like factor 7 deficiency disrupts corpus callosum development and neuronal migration in the developing mouse cerebral cortex.

Krüppel-like Factor 7 (KLF7) is a zinc finger transcription factor that has a critical role in cellular differentiation, tumorigenesis, and regeneration. Mutations in Klf7 are associated with autism spectrum disorder, which is characterized by neurodevelopmental delay and intellectual disability. Here we show that KLF7 regulates neurogenesis and neuronal migration during mouse cortical development. Conditional depletion of KLF7 in neural progenitor cells resulted in agenesis of the corpus callosum, defects in neurogenesis, and impaired neuronal migration in the neocortex. Transcriptomic profiling analysis indicated that KLF7 regulates a cohort of genes involved in neuronal differentiation and migration, including p21 and Rac3. These findings provide insights into our understanding of the potential mechanisms underlying neurological defects associated with Klf7 mutations.

Potential role of tanycyte-derived neurogenesis in Alzheimer's disease.

Tanycytes, specialized ependymal cells located in the hypothalamus, play a crucial role in the generation of new neurons that contribute to the neural circuits responsible for regulating the systemic energy balance. The precise coordination of the gene networks controlling neurogenesis in naive and mature tanycytes is essential for maintaining homeostasis in adulthood. However, our understanding of the molecular mechanisms and signaling pathways that govern the proliferation and differentiation of tanycytes into neurons remains limited. This article aims to review the recent advancements in research into the mechanisms and functions of tanycyte-derived neurogenesis. Studies employing lineage-tracing techniques have revealed that the neurogenesis specifically originating from tanycytes in the hypothalamus has a compensatory role in neuronal loss and helps maintain energy homeostasis during metabolic diseases. Intriguingly, metabolic disorders are considered early biomarkers of Alzheimer's disease. Furthermore, the neurogenic potential of tanycytes and the state of newborn neurons derived from tanycytes heavily depend on the maintenance of mild microenvironments, which may be disrupted in Alzheimer's disease due to the impaired blood-brain barrier function. However, the specific alterations and regulatory mechanisms governing tanycyte-derived neurogenesis in Alzheimer's disease remain unclear. Accumulating evidence suggests that tanycyte-derived neurogenesis might be impaired in Alzheimer's disease, exacerbating neurodegeneration. Confirming this hypothesis, however, poses a challenge because of the lack of long-term tracing and nucleus-specific analyses of newborn neurons in the hypothalamus of patients with Alzheimer's disease. Further research into the molecular mechanisms underlying tanycyte-derived neurogenesis holds promise for identifying small molecules capable of restoring tanycyte proliferation in neurodegenerative diseases. This line of investigation could provide valuable insights into potential therapeutic strategies for Alzheimer's disease and related conditions.